Stomach cancer (gastric cancer) is a malignant neoplasm arising from the stomach, of which more than 90% are adenocarcinomas; less common types include gastric lymphoma, gastrointestinal stromal tumor, and neuroendocrine tumors. Gastric cancer is the fifth most commonly diagnosed cancer and the fifth leading cause of cancer death worldwide, with an estimated 968,350 new cases and 659,853 deaths in 2022. Age-standardized incidence and mortality have declined for decades as Helicobacter pylori prevalence has fallen, but incidence remains highest in East Asia, Eastern Europe, and parts of Central and South America. In the United States, the median age at diagnosis is 68 years, men are affected nearly twice as often as women, and early-onset disease (diagnosis before age 50) is rising. Billroth performed the first successful gastrectomy for gastric cancer in 1881.

Gastric adenocarcinoma develops through two biologically distinct pathways. The intestinal type arises through the Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma), which is overwhelmingly initiated by chronic H. pylori infection. The diffuse type usually arises de novo and is centered on loss of E-cadherin; its hereditary form, hereditary diffuse gastric cancer, is caused by germline CDH1 pathogenic variants. H. pylori, an IARC Group 1 carcinogen, is associated with about 90% of non-cardia cancers. Other risk factors include tobacco smoking, heavy alcohol use, high-salt and salt-preserved foods, processed meat, obesity, prior partial gastrectomy, autoimmune gastritis/pernicious anemia, and family history; cardia and gastroesophageal junction cancers are more closely linked to obesity and gastroesophageal reflux disease. About 10% of cases show familial clustering, but only 1–3% are attributable to known germline variants. The Cancer Genome Atlas (TCGA) defines four molecular subtypes: Epstein-Barr virus–positive, microsatellite instability-high, genomically stable, and chromosomal instability. Gastric cancer is classified by anatomic site, TNM stage, histology (Laurén and WHO), macroscopic pattern (Borrmann and Paris), and molecular subtype, but only stage and predictive biomarkers currently change management.

Early gastric cancer is often asymptomatic. Advanced disease presents with abdominal pain, weight loss, early satiety, bloating, dysphagia, hematemesis, or melena. Signs of advanced or metastatic disease include Virchow’s node, Sister Mary Joseph nodule, Blumer’s shelf, the Leser-Trelat sign, and Trousseau’s syndrome. Gastric cancer must be differentiated from gastric lymphoma, gastric metastasis, gastritis, benign gastric ulcer, and Ménétrier’s disease. Endoscopic screening every 2–3 years is suggested in high-incidence regions, whereas in low-incidence regions such as the United States it is reserved for defined high-risk groups. Upper endoscopy with biopsy is the diagnostic test of choice. Staging uses the AJCC/UICC 8th edition TNM system, with separate clinical (cTNM), pathological (pTNM), and post-neoadjuvant (ypTNM) stage groups. Endoscopic ultrasonography is the most reliable method for assessing depth of invasion, contrast-enhanced CT evaluates distant spread, PET/CT helps characterize CT-detected lymphadenopathy, and staging laparoscopy detects occult peritoneal disease before neoadjuvant therapy. Stage is the strongest determinant of prognosis: five-year survival exceeds 90% for treated early gastric cancer but is poor for disseminated disease.

Endoscopic resection by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is the treatment of choice for early gastric cancer meeting Japanese Gastric Cancer Association criteria. Gastrectomy with D2 lymphadenectomy is standard for potentially curable T2–T4 tumors, and laparoscopic and robot-assisted approaches are oncologically equivalent to open surgery. For resectable cT2 or higher or node-positive disease, perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the preferred standard, and the addition of durvalumab improved event-free and overall survival in the MATTERHORN trial. For unresectable, recurrent, or metastatic disease, first-line systemic therapy is a fluoropyrimidine plus platinum backbone guided by biomarker testing: a PD-1 inhibitor (nivolumab or pembrolizumab) for HER2-negative tumors, trastuzumab (with pembrolizumab if PD-L1-positive) for HER2-positive tumors, and zolbetuximab for claudin 18.2-positive tumors. Later-line options include ramucirumab with or without paclitaxel, trastuzumab deruxtecan, and trifluridine/tipiracil. Palliative gastrectomy is not routinely recommended. Primary prevention centers on H. pylori eradication, smoking cessation, and a diet low in salt and rich in fruits and vegetables.

John Jones was the first to perform a gastric resection in animals. In 1881, Billroth’s first human surgery. In 1897, Schlatter has done the first esophago-enterostomy after gastrectomy. Between 1884 to 1929, Finney’s and Rienhoff were the first to perform partial gastrectomy showing less side effects and less mortality rates.

No single scheme captures all clinically relevant information about gastric cancer. In current practice, a gastric adenocarcinoma is described along several complementary axes:^[1][2]

• Anatomic site: non-cardia (true gastric) versus gastroesophageal junction (GEJ) tumors, with Siewert subtyping for junctional tumors
• Extent of disease: the AJCC/UICC 8th-edition TNM system, with separate clinical (cTNM), pathologic (pTNM), and post-neoadjuvant (ypTNM) stage groups
• Histology: the Laurén types and the WHO histologic subtypes
• Macroscopic pattern: the Borrmann classification for advanced tumors and the Paris/superficial classification for early tumors
• Molecular subtype: the TCGA and ACRG genomic classifications, plus the predictive biomarkers HER2, PD-L1, mismatch repair/microsatellite instability (MMR/MSI), and claudin 18.2 (CLDN18.2)
• Precursor lesions: gastric dysplasia graded by the WHO two-tier system and the Vienna classification

Only TNM stage and the predictive biomarkers currently change management. Histologic and molecular subtypes remain mainly descriptive and prognostic.^[3][4]

Gastric adenocarcinoma develops through two biologically distinct pathways. The intestinal-type pathway is driven by inflammation and progresses stepwise through the Correa cascade. It is overwhelmingly initiated by Helicobacter pylori. The diffuse-type pathway is largely de novo and is centered on loss of E-cadherin (CDH1).^[4][5][6] H. pylori is a WHO Group 1 carcinogen. Only about 1–3% of infected individuals develop cancer, which reflects the combined effect of bacterial virulence (particularly CagA), host genetics, and environmental cofactors.^[4][7]

The 2014 The Cancer Genome Atlas (TCGA) classification sits on top of the Lauren histologic dichotomy. It defines four subtypes:

• Chromosomal instability (CIN)
• Microsatellite instability (MSI)
• Epstein-Barr virus–positive (EBV+)
• Genomically stable (GS)

These subtypes are independently prognostic and underpin the biomarkers that direct targeted therapy and immunotherapy: mismatch repair (MMR)/MSI, HER2, PD-L1, and EBV.^[8][9][10]

About 10% of gastric cancers show familial aggregation, but only 1–3% are attributable to known germline variants. The most important of these is hereditary diffuse gastric cancer (HDGC), caused by germline CDH1 pathogenic variants. Contemporary penetrance estimates for HDGC are substantially lower than historical figures.^[4][2][11]

Gastric adenocarcinoma results from an interaction between chronic infection, environmental and dietary exposures, host genetic susceptibility, and, in a small minority, high-penetrance germline variants. Chronic Helicobacter pylori infection, an IARC group 1 carcinogen, is the dominant modifiable cause. It accounts for approximately 75% of attributable risk overall and approximately 90% of non-cardia (distal) cancers.^[4][12] Most intestinal-type cancers arise through the stepwise Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma). Diffuse-type cancers frequently arise without a recognizable precancerous lesion. When diffuse-type cancer is hereditary, it is driven by germline CDH1 (E-cadherin) inactivation.^[13] About 10% of cases show familial clustering, but only about 1–3% are attributable to a known heritable germline variant.^[2] The TCGA molecular classification (EBV-positive, MSI, genomically stable, chromosomal instability) has superseded older, undifferentiated oncogene lists as the framework for molecular etiology.^[8]

Stomach cancer must be differentiated from other diseases presenting with episodic abdominal pain, weight loss and loss of appetite such as gastric lymphoma, gastric metastasis, gastritis, benign gastric ulcer, Menetrier’s disease.

Gastric cancer is the fifth most commonly diagnosed cancer and the fifth leading cause of cancer death worldwide. GLOBOCAN estimated 968,350 new cases and 659,853 deaths in 2022.^[14][9] Age-standardized incidence and mortality have declined for more than half a century, mainly because Helicobacter pylori prevalence has fallen and food refrigeration and preservation have improved. Absolute case numbers keep rising because of population growth and aging.^[12] Incidence is highest in East Asia, Eastern Europe, and parts of Central and South America. In the United States, about 30,300 new cases are diagnosed each year, the median age at diagnosis is 68 years, and incidence in men is nearly twice that in women.^[9] Cardia and non-cardia gastric cancer are epidemiologically distinct diseases. The incidence of early-onset disease (diagnosis before age 50) is rising in several low-incidence countries, including the United States.^[4][9]

Risk for gastric adenocarcinoma (>90% of stomach cancers) is dominated by chronic Helicobacter pylori infection. H. pylori is an IARC Group 1 carcinogen and is associated with roughly 90% of non-cardia (gastric body and antrum) cancers.^[15][9] It drives the stepwise Correa cascade: chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma.^[4][12]

Other modifiable risk factors are tobacco smoking, heavy alcohol use, high dietary salt and salt-preserved foods, processed meat, and obesity. Nonmodifiable factors include older age, male sex, high-risk ancestry or immigration from high-incidence regions, prior partial gastrectomy, prior abdominal radiotherapy, autoimmune gastritis/pernicious anemia, and inherited predisposition. The most important inherited cause is a germline CDH1 pathogenic variant causing hereditary diffuse gastric cancer (HDGC).^[9]

Risk-factor profiles differ by anatomic site and histology:

• Non-cardia, intestinal-type cancer is overwhelmingly H. pylori–driven and arises from precancerous mucosal lesions.
• Cardia/gastroesophageal junction (GEJ) cancer is more closely linked to obesity and gastroesophageal reflux disease (GERD).^[12]
• Diffuse-type cancer can arise without a precursor inflammatory field. This includes the hereditary (CDH1) form.^[16]

Gastric cancer screening aims to detect adenocarcinoma at an early, curable stage and to identify gastric premalignant conditions along the Correa cascade: atrophic gastritis (AG), gastric intestinal metaplasia (GIM), and dysplasia.^[17]

How a population is screened depends on how common gastric cancer is in that region:

• High-incidence regions: endoscopic screening every 2–3 years is suggested.
• Low-incidence regions: general-population screening is not recommended.^[18]
• United States: screening endoscopy is considered only for defined high-risk groups.^[19]

Upper endoscopy (EGD) is the preferred screening test.^[19] In the Korean national program, EGD was associated with lower gastric cancer mortality, whereas the upper GI series (UGIS) was not.^[20]

The only randomized trial reported so far found a non-significant reduction in non-cardia gastric cancer mortality with endoscopic screening.^[21]

If left untreated, the five-year survival rates of gastric cancer range from almost no survival for patients with disseminated disease to almost 50% survival for patients with localized distal gastric cancers confined to resectable regions. Higher recurrence rates are seen in those who have piecemeal or incomplete resections. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor. Complications of gastric cancer are ascites, gastrointestinal bleeding, distant metastasis to other organs, weight loss, recurrence of cancer, and treatment complications. The prognosis of patients with gastric cancer is related to tumor extent that includes direct tumor extension and lymph nodes involvement. The five-year survival rate for treated early gastric cancer is over 90 percent; nearly 100 percent for mucosal tumors, and 80 to 90 percent for submucosal tumors.

Gastric adenocarcinoma is staged with the tumor–node–metastasis (TNM) system maintained jointly by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). The current standard is the AJCC 8th edition, implemented January 1, 2018. It is the version used in the NCCN Gastric Cancer Guidelines.^[22][3]

The 8th edition uses the same T, N, and M definitions in every setting. It provides three separate stage-grouping schemata for different points in care:

• clinical (cTNM), before treatment
• pathological (pTNM), after upfront resection
• post-neoadjuvant pathological (ypTNM), after preoperative therapy and resection^[23][16]

Stage determines the main treatment choice: endoscopic resection, surgery alone, perioperative multimodality therapy, or palliative systemic therapy. Stage is also the strongest determinant of prognosis.^[9]

Symptoms of stomach cancer include abdominal pain, bloating, weight loss, hematemesis, melena, and dysphagia. Twenty-five percent of patients have a history of gastric ulcer

Patients with stomach cancer generally appear weak. Common physical examination findings include abdominal distention, palpation of an abdominal mass, and pallor. Leser-Trelat sign and presence of Virchow’s node (left supraclavicular lymphadenopathy), Sister Mary Joseph nodule (visible periumbilical nodule), Blumer’s shelf (rectal mass/shelf on rectal exam) and/or Trousseau’s syndrome (migratory phlebitis) on physical examination are highly suggestive of stomach cancer

Laboratory findings in gastric cancer include anemia of chronic disease on complete blood count, liver function tests may reveal abnormalities in liver function tests, antigens such as carcinoembryonic antigen, glycoprotein CA 125, carbohydrate antigen 19-9, cancer antigen 72-4, alpha-fetoprotein

Biopsy may be helpful in the diagnosis of stomach cancer. It has a sensitivity of 98% to diagnose gastric cancer but may be negative in linitis plastica. It is commonly used nowadays as first line of treatment for superficial lesions.

Chest x-ray may show spread to the lungs as a cannon-ball appearance on radiography. Advanced gastric carcinoma may be visible on an abdominal x-ray as an uneven stomach contours or small masses indenting the stomach contours

Abdominal CT scan may be helpful in the diagnosis of stomach cancer. It is used to evaluate metastatic disease, especially hepatic or adnexal metastases, ascites, or distant nodal spread. Integrated PET/CT imaging can be useful to confirm malignant involvement of CT-detected lymphadenopathy. A negative PET CT is not helpful, since even large tumors with a diameter of several centimeters may not be visible on PET scan if the tumor cells have a fairly low metabolic activity.

MRI has better soft tissue sensitivity than CT.Individual layers may be better differentiated on MRI compared with CT. Hence, better T staging of stomach cancer. Water or effervescent granules are used to distend stomach to perform MRI

Endoscopic ultrasonography (EUS) is the most reliable diagnostic technique for evaluation of the depth of invasion of primary gastric cancers. Endoscopic ultrasonography is not the procedure of choice for detecting nodal spread.

Barium studies may be diagnostic of stomach cancer. The sensitivity of barium meals may be 14%. False-negative barium studies can occur in 50 percent of cases. There are three types of early gastric cancer which include polypoid, ulcerated, and superficial.

Laparoscopy has the advantage of directly visualizing the liver surface, the peritoneum, and local lymph nodes. Diagnostic laparoscopy is especially important for patients who are being considered for a trial of neoadjuvant therapy.

The optimal therapy for stomach cancer depends on the stage at diagnosis and, in advanced disease, increasingly on molecular biomarkers. For patients with resectable disease, perioperative chemotherapy with the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the preferred standard for medically fit patients, having demonstrated superior overall survival compared with the older epirubicin-based ECF/ECX regimen (median overall survival 50 versus 35 months) in the phase 3 FLOT4-AIO trial.^[24] The addition of perioperative immunotherapy with durvalumab to FLOT improved event-free survival (HR 0.71) and, at the final analysis, overall survival (HR 0.78; 95% CI 0.63–0.96; p=0.021) in the phase 3 MATTERHORN trial; no overall survival advantage was seen in the diffuse-type subgroup.^[25][26][3] Adjuvant chemoradiotherapy and adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin remain acceptable options, particularly where perioperative therapy was not given. Medical therapy is also indicated for patients with unresectable or recurrent disease, after non-curative R2 resection, unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination, or other M1 disease. Response to treatment should be evaluated by examinations such as CT scan, endoscopy, and contrast radiography. For unresectable, recurrent, or metastatic disease, systemic therapy is guided by biomarker testing for HER2 overexpression, programmed death-ligand 1 (PD-L1) combined positive score (CPS), claudin 18.2 (CLDN18.2), and mismatch repair/microsatellite instability (MMR/MSI) status. First-line therapy uses a fluoropyrimidine plus platinum backbone, to which a PD-1 inhibitor (nivolumab or pembrolizumab) is added in HER2-negative disease, trastuzumab is added in HER2-positive disease (with pembrolizumab for PD-L1–positive HER2-positive tumors), and zolbetuximab is added for CLDN18.2-positive tumors. For locally advanced unresectable and metastatic tumors, the goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival; later-line options include ramucirumab with or without paclitaxel, trastuzumab deruxtecan for HER2-positive disease, and trifluridine/tipiracil.

Surgery remains the only potentially curative treatment for stomach cancer and is central to the multidisciplinary management of gastric cancer. Endoscopic resection is the treatment of choice for early gastric cancer meeting absolute or expanded indication criteria, as defined by the Japanese Gastric Cancer Association (JGCA) 2021 (6th edition) treatment guidelines.^[27] Methods for endoscopic resection include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Side effects of endoscopy include bleeding and perforation. For T1 tumors, a gross resection margin of 2 cm should be obtained. A proximal margin of at least 3 cm is recommended for T2 or deeper tumors with an expansive growth pattern and 5 cm for those with an infiltrative growth pattern. For tumors invading the esophagus, a 5-cm margin is not necessarily required, but intraoperative frozen section examination of the resection line is preferred to confirm an R0 resection.

Lymph node dissection is defined by extent. D1 lymphadenectomy refers to dissection of only the perigastric lymph nodes (stations 1-7). D1+ lymphadenectomy adds stations 8a, 9, and (for total gastrectomy) 11p to the D1 dissection and is used for cT1 tumors not indicated for D1 alone. D2 lymphadenectomy is an extended lymph node dissection that additionally removes nodes along the hepatic, left gastric, celiac, and splenic arteries, and, when indicated, the splenic hilum; it is the standard of care for potentially curable T2-T4 tumors. D3 (super-extended) dissection adds D2 plus removal of nodes within the porta hepatis and para-aortic regions; prophylactic para-aortic dissection added to D2 did not improve survival in the randomized JCOG9501 trial and is not routinely recommended outside clinical trials.^[28]

Laparoscopic and robot-assisted minimally invasive gastrectomy with D2 lymphadenectomy are now supported by long-term randomized data as oncologically equivalent, and in some outcomes superior, alternatives to open gastrectomy for both early and locally advanced gastric cancer.^[29][30][31] For resectable locoregional adenocarcinoma (cT2 or higher, or node-positive), perioperative systemic chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) — now increasingly combined with the anti-PD-L1 monoclonal antibody durvalumab — has replaced older anthracycline-based (ECF/MAGIC) regimens as the perioperative standard of care.^[24][25] For metastatic disease, gastrectomy is not routinely recommended for palliation alone, based on the randomized REGATTA trial, and first-line systemic therapy — chemotherapy plus the anti-PD-1 monoclonal antibody nivolumab in appropriate candidates — is preferred over surgery-first approaches.^[32][33]

Effective measures for the primary prevention of stomach cancer include smoking cessation, eradication of Helicobacter pylori infection, and having a balanced diet rich in fruits and vegetables. In areas of low gastric cancer, incidence and screening for gastric cancer with upper endoscopy should be reserved for specific high-risk subgroups. Individuals at increased risk for gastric cancer include gastric adenomas, pernicious anemia, gastric intestinal metaplasia, familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome.

Gastric cancer secondary prevention is indicated for all patients after gastric surgeries. Physical examination, complete blood count, imaging or endoscopy are indicated to decrease chances of recurrence.

John Jones was the first to perform a gastric resection in animals. In 1881, Billroth’s first human surgery. In 1897, Schlatter has done the first esophago-enterostomy after gastrectomy. Between 1884 to 1929, Finney’s and Rienhoff were the first to perform partial gastrectomy showing less side effects and less mortality rates.

• Around 1800, Dr. John Jones was the first to perform a gastric resection in animals ^[1]
• In 1881, Billroth’s performed the first human gastric surgery ^[2]
• In 1885, Billroth developed a second resection method. He used anterior gastro-enterostomy that was called Billroth II operation^[3]
• In 1897, Schlatter has done the first esophago-enterostomy after gastrectomy^[4]
• In 1898, a successful gastrectomy was performed on a patient without any complications by Mcdonald.^[5]
• Gastric cancer was the most common cancer in 1990 In 1990^[6]
• Between 1884 to 1929, Finney’s and Rienhoff were the first to perform partial gastrectomy showing fewer side effects and fewer mortality rates^[7]
• In 1940s, Coller, Kay, and McIntyre published a study of all regional lymph nodes^[8]
• Between November 1950 and January 1953, Sunderland et al. studied lymph node metastasis associated with gastric cancer^[9]

No single scheme captures all clinically relevant information about gastric cancer. In current practice, a gastric adenocarcinoma is described along several complementary axes:^[1][2]

• Anatomic site: non-cardia (true gastric) versus gastroesophageal junction (GEJ) tumors, with Siewert subtyping for junctional tumors
• Extent of disease: the AJCC/UICC 8th-edition TNM system, with separate clinical (cTNM), pathologic (pTNM), and post-neoadjuvant (ypTNM) stage groups
• Histology: the Laurén types and the WHO histologic subtypes
• Macroscopic pattern: the Borrmann classification for advanced tumors and the Paris/superficial classification for early tumors
• Molecular subtype: the TCGA and ACRG genomic classifications, plus the predictive biomarkers HER2, PD-L1, mismatch repair/microsatellite instability (MMR/MSI), and claudin 18.2 (CLDN18.2)
• Precursor lesions: gastric dysplasia graded by the WHO two-tier system and the Vienna classification

Only TNM stage and the predictive biomarkers currently change management. Histologic and molecular subtypes remain mainly descriptive and prognostic.^[3][4]

Non-cardia and cardia/GEJ cancers differ in epidemiology, etiology, and treatment. Location should therefore be assigned first.^[1] Adenocarcinomas involving the GEJ are subtyped by the Siewert classification, which uses the position of the tumor epicenter relative to the anatomic junction.^[5][3]

• Under the AJCC 8th edition, a tumor that involves the EGJ and has its epicenter no more than 2 cm into the proximal stomach is staged as esophageal. A tumor with its epicenter more than 2 cm distal to the EGJ is staged as gastric, even if the EGJ is involved.^[6][7]
• Genomically, Siewert type I and II tumors resemble lower esophageal adenocarcinoma: they are predominantly chromosomal-instability (CIN) tumors with Barrett metaplasia and p53 pathway dysregulation. Siewert type III tumors share features with gastric cancer, which supports staging them as gastric.^[7]

The AJCC/UICC 8th edition, implemented in 2018, is the main classification used for prognosis and treatment selection. It defines separate stage groups for clinical (cTNM), pathologic (pTNM), and post-neoadjuvant (ypTNM) settings. Using the stage group that matches the clinical setting avoids misclassification.^[8][6][3]

Key changes from the 7th edition:^[6][9]

• N3 was formally split into N3a and N3b for stage grouping. As a result, T1N3b, T2N3b, and T3N3b were upstaged, and several T4 combinations were downstaged.
• Separate clinical and post-neoadjuvant (ypTNM) stage groupings were introduced.
• Siewert type III tumors were reassigned from esophageal to gastric staging.
• In Korean and SEER validation cohorts, the 8th edition predicted survival more accurately than the 7th edition and produced more homogeneous stage IIB–IIIC subgroups.^[9]

The Laurén classification (1965) remains the scheme most widely used for subgroup analysis in clinical trials, although its independent predictive value is limited.^[10][1][2]

Morphology remains the basis of diagnosis, and the predominant histologic pattern defines the subtype. The WHO 6th edition (2026) moves toward an integrated histomolecular framework. It incorporates genotype–phenotype correlation and requires predictive-biomarker assessment.^[11][12]

• A European consensus defines signet-ring cell carcinoma within the PCC category as a tumor made up of more than 90% signet-ring cells. The consensus also recommends classifying tumors according to the current WHO edition.^[13]
• WHO terminology has changed over successive editions. Signet-ring cell carcinoma was folded into poorly cohesive carcinoma in the 4th edition, mixed adenocarcinoma was recognized in the 5th edition, and PCC was subclassified in the 6th edition.^[11]

The Borrmann classification (1926) describes the gross growth pattern of advanced gastric cancer and is associated with molecular features, disease extent, and survival.^[14][15]

Early gastric cancer is described with the superficial (type 0) classification rather than the Borrmann system.^[16][14][2]

• 0-I: protruded
• 0-II: superficial, subdivided into 0-IIa (elevated), 0-IIb (flat), and 0-IIc (depressed)
• 0-III: excavated

^[17][2]

The ACRG classification is expression-based. It was developed and validated in East Asian cohorts and stratifies prognosis more strongly than TCGA.^[18]

• TCGA and ACRG overlap with Laurén/WHO histology: GS corresponds broadly to diffuse histology, and CIN and MSI to intestinal histology. However, the two genomic systems do not map cleanly onto each other. In addition, TCGA subtypes stratify survival only weakly in Asian (ACRG) cohorts.^[18][2]
• Neither system is used for routine treatment selection. Prognostic and predictive validity is robust mainly for the MSI and EBV subtypes.^[4]

These biomarkers are the molecular classifiers that currently change management.^[3][19]

• NCCN recommends universal MMR/MSI and PD-L1 testing at diagnosis, and HER2 and CLDN18.2 testing in documented or suspected advanced or metastatic adenocarcinoma.^[3]

Gastric dysplasia (non-invasive epithelial neoplasia) is the recognized precursor of intestinal-type adenocarcinoma. It is graded with the WHO two-tier system:^[23][12]

• Low-grade dysplasia (LGD)
• High-grade dysplasia (HGD)
• “Indefinite for dysplasia” is used when inflammation or regenerative change obscures interpretation.

This two-tier system replaced the older three-tier (mild/moderate/severe) grading. Earlier schemes such as the Padova international classification and the Japanese Group I–V biopsy categories have been largely superseded by the Vienna and WHO systems.^[24][23]

^[23][25]

• The Vienna scheme was created to reconcile a long-standing East–West discrepancy. Japanese pathologists diagnose “adenocarcinoma” on cytoarchitectural atypia alone, whereas Western/WHO pathologists reserve “carcinoma” for invasive lesions.^[23][26]

• Gastric dysplasia, intestinal-type adenomas, and gastric-type adenomas are consolidated into a single “gastric dysplasia” section, mirroring the MAPS III management framework.^[27][12]
• Surface epithelium–derived lesions are divided into:^[27]
  • Intestinal-type
  • Foveolar-type, including indolent flat-elevated and “raspberry-type” lesions in H. pylori-naïve stomachs
  • Serrated dysplasia/adenoma
• Subsurface lesions are classified separately: pyloric gland adenoma, oxyntic gland adenoma, and pit/crypt dysplasia.^[27]
• Serrated dysplasia is rare but high-risk and warrants complete resection.^[27]
• Interobserver variability is substantial, especially for indefinite and low-grade lesions. Dysplasia should be confirmed by an experienced GI pathologist, and active H. pylori should be eradicated before definitive grading.^[28]

^[17][18][11]

• The prognostic value of histologic subtype varies across studies, partly because classification is applied inconsistently. This is particularly true for signet-ring cell tumors.^[2]
• Genomic classifications derive largely from resected primary tumors. Data on metastases and premalignant lesions are limited.^[4]
• Whether Siewert type II tumors should be managed with an esophageal or a gastric approach remains debated, and molecular profiling may eventually supplement purely anatomic GEJ classification.^[7]
• East–West diagnostic criteria for dysplasia and early cancer still diverge despite the Vienna consensus. Management of low-grade non-invasive neoplasia (surveillance versus endoscopic resection) is not uniformly defined.^[26]
• HER2 heterogeneity limits the reproducibility of HER2 classification in gastric cancer compared with breast cancer.^[21]

Gastric adenocarcinoma develops through two biologically distinct pathways. The intestinal-type pathway is driven by inflammation and progresses stepwise through the Correa cascade. It is overwhelmingly initiated by Helicobacter pylori. The diffuse-type pathway is largely de novo and is centered on loss of E-cadherin (CDH1).^[1][2][3] H. pylori is a WHO Group 1 carcinogen. Only about 1–3% of infected individuals develop cancer, which reflects the combined effect of bacterial virulence (particularly CagA), host genetics, and environmental cofactors.^[1][4]

The 2014 The Cancer Genome Atlas (TCGA) classification sits on top of the Lauren histologic dichotomy. It defines four subtypes:

• Chromosomal instability (CIN)
• Microsatellite instability (MSI)
• Epstein-Barr virus–positive (EBV+)
• Genomically stable (GS)

These subtypes are independently prognostic and underpin the biomarkers that direct targeted therapy and immunotherapy: mismatch repair (MMR)/MSI, HER2, PD-L1, and EBV.^[5][6][7]

About 10% of gastric cancers show familial aggregation, but only 1–3% are attributable to known germline variants. The most important of these is hereditary diffuse gastric cancer (HDGC), caused by germline CDH1 pathogenic variants. Contemporary penetrance estimates for HDGC are substantially lower than historical figures.^[1][8][9]

• Gastric adenocarcinoma arises when chronic injury, infection, and accumulated genomic and epigenomic damage shift gastric epithelial cells toward:^[1][10]
  • Reduced apoptosis
  • Increased proliferation
  • Aberrant differentiation
• Helicobacter pylori is the dominant cause of gastric adenocarcinoma.
  • Population-attributable risk is approximately 75% overall and approximately 89–90% for non-cardia cancer.^[1][4][2]
  • In a prospective Japanese cohort, gastric cancer developed in infected individuals but not in uninfected individuals.^[11]
  • A causal-inference analysis of 6.8 million Koreans estimated that H. pylori infection raised gastric cancer risk approximately 6-fold (RR 6.40, 95% CI 6.05–6.77).^[12]
• Cofactors that amplify risk among infected individuals include:^[13]
  • More virulent strains
  • Pro-inflammatory host genotypes
  • High-salt or smoked diets
  • Low iron levels
  • Smoking
• Hypochlorhydria from parietal cell loss permits colonization by pro-inflammatory, genotoxic non-H. pylori gastric microbiota.^[13][14]

The Correa cascade describes the stepwise histologic progression of intestinal-type gastric carcinogenesis:^[15][2]

• Progression risk:
  • Annual progression from intestinal metaplasia to cancer is low, approximately 0.13–0.3% per year.
  • Risk is highest with incomplete (type III) metaplasia and with extensive corpus involvement (antrum plus corpus).^[2][16][17]
• CagA and the type IV secretion system:
  • The cag pathogenicity island encodes a type IV secretion system that injects CagA into epithelial cells.
  • CagA is phosphorylated at EPIYA motifs and binds SHP-2.
  • It then aberrantly activates ERK–MAPK, Wnt/β-catenin, STAT3, and Hippo/YAP signaling.
  • The result is increased proliferation, inhibition of apoptosis, invasion, and stem-cell expansion.^[4][18][19]
  • CagA-positive strains confer higher cancer risk than CagA-negative strains.^[4][13]
• Inflammation and genotoxicity:
  • VacA (notably s1/m1 genotypes), lipopolysaccharide, peptidoglycan, and neutrophil-activating protein amplify NF-κB-driven inflammation.
  • This inflammation generates reactive oxygen and nitrogen species that cause DNA double-strand breaks and genomic instability.^[4][20][21]
  • Current evidence does not support nitric oxide alone as the principal mediator.
• Epigenetic field cancerization:
  • H. pylori-induced inflammation upregulates DNA methyltransferases and activation-induced cytidine deaminase.
  • This causes promoter hypermethylation and silencing of tumor-suppressor genes, including CDH1, CDKN2A/p16, and MLH1.
  • Somatic TP53 mutations also accumulate.
  • These field changes can persist after the organism is eradicated.^[10][22]
• Driver mutations: TP53, KRAS, and APC/Wnt-pathway alterations accumulate as dysplasia emerges.^[10][23]
• Refinement of the cascade: Single-cell and lineage-tracing studies add several cellular-level layers beneath the tissue-level sequence:^[23][24][25]
  • Spasmolytic polypeptide-expressing metaplasia (SPEM)
  • Pyloric metaplasia
  • Stem-cell plasticity
  • Non-sequential and parallel trajectories
• Effect of eradication: Eradication of H. pylori reduces cancer incidence but has limited, if any, effect on established intestinal metaplasia.^[17][26]

• Initiating event: Loss of E-cadherin (CDH1) initiates diffuse-type cancer.
  • Tumors are poorly cohesive.
  • Intracytoplasmic mucin displaces the nucleus, producing signet-ring cells.
  • Diffuse mural infiltration produces linitis plastica.^[1][2][3]
• No defined precursor: Unlike intestinal-type disease, there is no well-defined precursor cascade. Tumors arise at a younger age and carry a worse prognosis.^[1][27]
• Mechanism:
  • E-cadherin is lost through somatic mutation, loss of heterozygosity, and promoter hypermethylation.
  • Loss destabilizes adherens junctions and disrupts cell polarity and tension sensing.
  • This enables epithelial–mesenchymal transition and single-cell invasion.^[28][25]
  • In murine models, E-cadherin loss in CD44+ gastric cells alone is sufficient to initiate multifocal signet-ring carcinoma. TP53 loss mainly accelerates progression.^[28]
• Molecular correlate: Diffuse-type disease maps closely onto the TCGA genomically stable subtype, which is enriched for CDH1 and RHOA mutations and CLDN18–ARHGAP fusions.^[5][29]
• Open question: Whether diffuse-type cancer is purely de novo, or shares early injury and field effects with the intestinal pathway, remains unresolved.^[25][3]

• Burden: EBV is present in approximately 8–10% of gastric cancers worldwide, which is the largest absolute burden of any EBV-associated malignancy.^[30]
• Clonality: Tumor cells carry a monoclonal EBV genome, which implies transformation from a single infected cell.^[30][31]
• Mechanism:
  • Latent viral products (EBNA1, LMP2A, EBERs, and BART miRNAs) drive DNA methyltransferase upregulation.
  • This produces an extreme CpG-island methylator phenotype (CIMP) that silences tumor-suppressor genes.
  • PIK3CA mutations and PD-L1/PD-L2 (CD274/PDCD1LG2) amplification are characteristic.
  • TP53 is usually wild-type.^{[5][31][32][14]}
• Phenotype: EBV+ tumors are typically:^[31][32][33]
  • Proximal in location
  • More common in men
  • Poorly differentiated with dense lymphoid stroma
  • Associated with lower nodal metastasis
  • Highly sensitive to immunotherapy
• Prognosis: Most data favor a better prognosis, but at least one analysis found no significant survival effect.^[33][34]

Molecular subtype reflects tumor biology better than histology or anatomic location.^[5][6][35] In a Memorial Sloan Kettering cohort of 1,438 patients, TCGA subtype was independently associated with cancer-specific survival after adjustment for stage and grade. Subtype was also more influential than tumor location in predicting treatment response.^[7]

• Anatomic distribution: GS and EBV+ tumors favor the proximal stomach, CIN concentrates at the gastroesophageal junction and cardia, and MSI favors the antrum.^[6][36]
• ACRG classification: The Asian Cancer Research Group (ACRG) scheme defines four subtypes and overlaps substantially with TCGA:^[8][39][38]
  • MSI
  • MSS/EMT (mesenchymal-like)
  • MSS/TP53-active
  • MSS/TP53-inactive
• The distinctive ACRG contribution is the MSS/EMT subtype. It is characterized by CDH1 loss, CLDN18–ARHGAP fusions, strong peritoneal-metastasis propensity, and the worst prognosis.
• Limitations in routine practice: TCGA and ACRG subtypes are not yet routine treatment determinants.
  • In current practice, only MMR/MSI, HER2, PD-L1 (combined positive score), and increasingly EBV status are tested.
  • Both classifications derive mainly from resected primary tumors, with sparse data on premalignant and metastatic lesions.^[1][8]

• Second hit: Neoplastic transformation requires somatic inactivation of the second CDH1 allele.^[28]
• Occult intramucosal foci:
  • Nearly all carriers harbor microscopic intramucosal (pT1a) signet-ring cell foci.
  • The rate at which these foci progress to advanced cancer is poorly defined.^[28][40]
• Penetrance has been revised downward:
  • Historical estimates from high-risk kindreds were approximately 70% in men and 56% in women.^[41]
  • NCCN-endorsed cumulative risks through age 80 are approximately 37–42% in men and 25–33% in women.^[40]
  • In a North American cohort of families with CDH1 variants, lifetime cumulative risk of advanced gastric cancer was 10.3% in male carriers and 6.5% in female carriers.^[9]
  • Risk is substantially higher with a strong family history; the estimate was 38% with 3 or more affected first-degree relatives.^[9]
• Breast cancer risk: Female carriers have an approximately 37–55% lifetime risk of lobular breast cancer, which requires separate surveillance.^[9][42]
  • In a genotype-first European multicenter study, CDH1 pathogenic and likely pathogenic variants were positively associated with diffuse gastric cancer and lobular breast cancer.
  • No such association was found for missense variants of uncertain significance.^[43]
• Surveillance limitations and surgery:
  • Surveillance endoscopy has limited sensitivity for multifocal superficial signet-ring foci and usually cannot distinguish pT1a from pT1b disease.
  • Carriers are therefore offered risk-reducing total gastrectomy, typically between ages 20 and 30.
  • Surveillance is reserved for carriers who defer surgery.^{[27][40][44][45]}
• Decision-making: No genotype–phenotype predictor exists, and risk varies widely between families. Surgery-versus-surveillance decisions are therefore increasingly individualized.^[9][40]

• Lauren classification:^[1][3][22]
  • Intestinal type: Gland-forming tumors arising on a background of atrophy and intestinal metaplasia. They are associated with H. pylori and occur predominantly in older men.
  • Diffuse type: Poorly cohesive, often signet-ring cells infiltrating singly. Extensive mural infiltration produces a rigid, thickened stomach wall (linitis plastica).
• Combined use: The Lauren classification combined with molecular subtyping, rather than exhaustive histologic typing schemes, is what currently informs trials and management.^[1][39]

• 
  Diffuse-type gastric adenocarcinoma producing linitis plastica (diffuse mural thickening). Case courtesy of Dr Andrew Ryan, Radiopaedia.org, rID: 16159
• 
  Poorly differentiated gastric adenocarcinoma (H&E, 400×). Public Domain, https://commons.wikimedia.org/w/index.php?curid=182915
• 
  Signet-ring cell carcinoma: intracytoplasmic mucin displaces the nucleus to the cell periphery. CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=502927

• Test and treat H. pylori: Testing and eradication are indicated in patients with gastric neoplasia, premalignant lesions, or a family history of gastric cancer.
  • Eradication reduces cancer incidence and the risk of metachronous cancer.
  • It incompletely reverses established metaplasia, so endoscopic surveillance remains necessary in high-risk mucosa.^[1][29][17]
• High-risk premalignant mucosa: The following features identify mucosa at highest risk:^[2][17]
  • Extensive (antrum plus corpus) atrophy or intestinal metaplasia
  • Incomplete intestinal metaplasia
  • Persistent H. pylori infection
  • Age older than 50
  • Family history of gastric cancer
• Biomarker testing: Testing of gastric adenocarcinoma for MMR/MSI, HER2, PD-L1, and EBV follows directly from subtype biology.^[6][8][7]
  • MSI-high and EBV+ tumors predict checkpoint-inhibitor benefit.
  • HER2 amplification (CIN subtype) directs trastuzumab-based therapy.
• Suspected HDGC: Patients should be referred to expert centers for CDH1/CTNNA1 testing and genetic counseling.^[40][27]

• Role of intestinal metaplasia: Whether metaplasia is an independent “point of no return” or a bystander is debated, as is which subset progresses. Chromosomal-instability features within metaplasia may identify progressors.^[16][17][23]
• Natural history in CDH1 carriers: The progression rate from pT1a foci to advanced cancer, and the optimal timing of gastrectomy versus surveillance, remain uncertain.^[9][40]
• Prognostic weight of EBV: The independent prognostic weight of EBV positivity is unsettled.^[33][34]
• Origin of diffuse-type cancer: Whether it is purely de novo or shares an early field effect with the intestinal pathway is not established.^[25]

Gastric adenocarcinoma results from an interaction between chronic infection, environmental and dietary exposures, host genetic susceptibility, and, in a small minority, high-penetrance germline variants. Chronic Helicobacter pylori infection, an IARC group 1 carcinogen, is the dominant modifiable cause. It accounts for approximately 75% of attributable risk overall and approximately 90% of non-cardia (distal) cancers.^[1][2] Most intestinal-type cancers arise through the stepwise Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma). Diffuse-type cancers frequently arise without a recognizable precancerous lesion. When diffuse-type cancer is hereditary, it is driven by germline CDH1 (E-cadherin) inactivation.^[3] About 10% of cases show familial clustering, but only about 1–3% are attributable to a known heritable germline variant.^[4] The TCGA molecular classification (EBV-positive, MSI, genomically stable, chromosomal instability) has superseded older, undifferentiated oncogene lists as the framework for molecular etiology.^[5]

• H. pylori is the single most important and most modifiable cause of gastric adenocarcinoma.
  • IARC classified it as a group 1 carcinogen in 1994 and reaffirmed this classification in 2009.^[2][6]
• Attributable risk: approximately 75% of global gastric cancer and approximately 90% of non-cardia cancers. In Japan, fewer than 1% of gastric adenocarcinomas are considered unrelated to H. pylori.^[1][7]
• Anatomic specificity: the association is strong for non-cardia cancer (pooled OR approximately 2.97) and essentially null for cardia cancer (OR approximately 0.99).^[8]
• Test method affects measured risk: serology reflects lifetime infection and yields higher odds ratios than histology. Histology underestimates infection when atrophic gastritis has reduced the bacterial load.^[2]
• Low absolute risk per infected person: about 44% of adults worldwide are infected, but only about 1–3% of infected individuals develop gastric cancer. Strain virulence, host genetics, and co-exposures modulate this risk.^[1][9]
• Mechanism (Correa cascade): chronic infection causes the following changes, which drive progression from normal mucosa to carcinoma:^[10][11]
  • Sustained NF-κB-mediated inflammation (IL-1β, IL-6, IL-8, TNF-α)
  • Oxidative and nitrosative DNA damage
  • Aberrant promoter hypermethylation (CDKN2A, MLH1, CDH1)
  • Induction of activation-induced cytidine deaminase, with TP53 mutation
• Virulence factors: CagA (delivered through the type IV secretion system) and VacA, particularly the s1/m1 genotype, confer substantially higher risk than less virulent strains.^[11] CagA also activates the NLRP3 inflammasome, which shapes immune-cell infiltration in gastric cancer.^[12]
• Histologic subtype: H. pylori is associated with both intestinal-type and diffuse-type cancer. Chronic inflammation is not required for diffuse-type carcinogenesis, which implies a distinct mechanism.^[1]
• Causal evidence: a cluster-randomized trial in Linqu County, China, enrolled 180,284 participants with 11.8 years of follow-up. Community-based eradication reduced gastric cancer incidence (intention-to-treat HR 0.86; 95% CI 0.74–0.99). The effect was larger among participants with confirmed eradication (HR 0.81; 95% CI 0.69–0.96).^[13][14]

• EBV is associated with approximately 5–10% of gastric cancers.^[1][9]
• EBV-positive tumors have the following features:^[1][5]
  • Location in the proximal stomach
  • Occurrence in younger patients
  • Dense immune infiltration with PD-L1/PD-L2 expression
  • Extensive DNA hypermethylation
  • Recurrent PIK3CA, ARID1A, and BCOR mutations

Environmental exposures are believed to drive most non-hereditary cases.^[15]

• Other associations: older age, male sex, lower socioeconomic status, poor hygiene, pernicious anemia, and prior gastric ulcer or partial gastrectomy.^[1][17]
• Chronic atrophic gastritis and intestinal metaplasia are intermediate risk states on the causal pathway, not independent exposures.^[1]
• The rising incidence of early-onset gastric cancer (age <50 years) is incompletely explained by known risk factors.^[9]

• Hereditary gastric cancer is traditionally divided into three autosomal dominant syndromes:^[4]
  • Hereditary diffuse gastric cancer (HDGC)
  • Familial intestinal gastric cancer
  • Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

• HDGC is an autosomal dominant syndrome of early-onset diffuse gastric cancer and lobular breast cancer. It is caused mainly by inactivating germline CDH1 variants.^[18][19]
  • Pathogenic CDH1 variants occur in approximately 1 in 5,000 to 1 in 8,000 people in unselected populations.^[19]
• Mechanism: CDH1 encodes E-cadherin, a transmembrane cell–cell adhesion protein and tumor suppressor.
  • Carriers inherit one inactivated allele.
  • A somatic second hit (mutation, loss of heterozygosity, or promoter hypermethylation) inactivates the remaining allele.
  • Loss of E-cadherin function produces poorly cohesive signet ring cell carcinoma.^[19][20][21]
• Current penetrance estimates (lower than older pedigree-based figures of approximately 70% in men and 56% in women):^[18][19]
  • Cumulative gastric cancer risk to age 80: approximately 37–42% in men and 25–33% in women
  • Lobular breast cancer risk in women: 37–55%
• Intramucosal foci: nearly all carriers harbor microscopic intramucosal (pT1a) signet ring cell foci. Cancer of any stage is found in 88–97% of risk-reducing gastrectomy specimens, but disease ≥pT1b is found in only about 2–3%. Modeled lifetime risk of advanced (≥stage 2) cancer is approximately 10% in men and 6.5% in women.^[19]
• Other HDGC genes: CTNNA1 (α-E-catenin) accounts for approximately 2% of HDGC families. About 70% of clinically defined HDGC families have no identified causative gene.^[3][4]

The TCGA classification defines four molecular subtypes with distinct causal mechanisms.^[5]

• The Asian Cancer Research Group (ACRG) proposed an overlapping classification: MSI, MSS/EMT, MSS/TP53-active, and MSS/TP53-inactive. Its distinct MSS/EMT subtype is marked by CDH1 loss and peritoneal tropism.^[22]
• In routine practice, formal subtype assignment is not yet standard. Only actionable markers are tested: MMR/MSI, HER2, PD-L1, and increasingly EBV and Claudin-18.2.^[4][23]
  • Up to about 25% of GEJ tumors fall outside the expected CIN class.^[24]

• Apply the H. pylori causal link to non-cardia cancer only. Cardia and GEJ cancers are instead linked to obesity, reflux, and Barrett’s esophagus.^[8][7]
• A single negative histologic H. pylori test can be falsely negative in atrophic gastritis or intestinal metaplasia; serology captures lifetime infection.^[2]
• Diffuse-type cancer often does not follow the Correa cascade.^[1]
• The following findings should prompt germline CDH1 evaluation per NCCN criteria:^[19]
  • Diffuse gastric cancer or T1a signet ring cell carcinoma at any age
  • Diffuse gastric cancer diagnosed before age 50
  • Lobular breast cancer with a personal or family history of diffuse gastric cancer
  • Qualifying family histories

Stomach cancer must be differentiated from other diseases presenting with episodic abdominal pain, weight loss and loss of appetite such as gastric lymphoma, gastric metastasis, gastritis, benign gastric ulcer, Menetrier’s disease.

Stomach cancer must be differentiated from other diseases presenting with episodic abdominal pain, weight loss and loss of appetite. The differentials include the following:^{[1][2][3][4][5][6][7][8][9]}

Gastric cancer is the fifth most commonly diagnosed cancer and the fifth leading cause of cancer death worldwide. GLOBOCAN estimated 968,350 new cases and 659,853 deaths in 2022.^[1][2] Age-standardized incidence and mortality have declined for more than half a century, mainly because Helicobacter pylori prevalence has fallen and food refrigeration and preservation have improved. Absolute case numbers keep rising because of population growth and aging.^[3] Incidence is highest in East Asia, Eastern Europe, and parts of Central and South America. In the United States, about 30,300 new cases are diagnosed each year, the median age at diagnosis is 68 years, and incidence in men is nearly twice that in women.^[2] Cardia and non-cardia gastric cancer are epidemiologically distinct diseases. The incidence of early-onset disease (diagnosis before age 50) is rising in several low-incidence countries, including the United States.^[4][2]

• GLOBOCAN 2022 ranked gastric cancer fifth worldwide in both incidence and mortality, with 968,350 new cases and 659,853 deaths.^[1][2]
• In the Global Burden of Disease (GBD) 2021 analysis, the global age-standardized incidence rate (ASIR) was 14.33 per 100,000, down from 24.76 per 100,000 in 1990. The age-standardized mortality rate (ASMR) was 11.20 per 100,000.^[5]
• Over the same period, absolute incident cases rose from about 981,000 (1990) to about 1.23 million (2021).^[5]
• Different modeling frameworks give different absolute counts, so figures should always be cited with their source and year rather than averaged:^[1][5]

• Incidence is highest in East Asia (China, Japan, South Korea), Eastern Europe, and parts of Central and South America. It is lowest in North America and most of Africa.^[3]
• In 2020, incidence was about 22.4 per 100,000 in Eastern Asia, compared with about 4.2 per 100,000 in North America and 3–4 per 100,000 in Africa.^[3]
• Asia accounts for about 75% of global cases and deaths. In GBD 2021, China alone accounted for about 612,000 cases.^[7][8]
• Development gradient: Incidence tracks H. pylori prevalence. Mortality is proportionally higher in medium- and low-HDI regions because of late diagnosis and limited access to treatment.^[3]
• Migration: First-generation immigrants from high-incidence countries keep up to ~5-fold higher incidence and ~2-fold higher mortality than the low-incidence host population. The excess shrinks in later generations.^[9] Classic studies of Japanese migrants to the United States first showed that early-life environmental exposures, rather than genetics, drive most of this risk.^[10]

• Age-standardized incidence and mortality have fallen worldwide. The global ASIR dropped by roughly 30–40% between 1990 and 2021.^[5]
• In the United States, age-standardized incidence fell by about 1.46% per year from 1975 to 2019 (11.6 to 6.1 per 100,000).^[3] The decline was about 0.94% per year between 2001 and 2015.^[11]
• Rates are falling while counts are rising, because aging and population growth outweigh the falling rates. This has direct implications for service planning.^[3]

• Estimates for 2025 are about 30,300 new cases and 10,780 deaths.^[2]
• Five-year relative survival across all stages rose from 15% in 1977 to about 36% by 2020.^[2]
• Survival depends strongly on stage: about 70% for localized, 31% for regional, and 6% for distant disease. About 60% of patients present with regional or distant disease.^[12] Early-stage disease amenable to endoscopic or surgical resection has a 5-year relative survival of about 75%.^[2]
• Mortality fell substantially across all racial and ethnic groups from 2000 to 2019. It was lowest in the White population every year, and minoritized populations had higher mortality in almost all counties.^[12]
• Gastric cancer mortality is 43% higher in U.S. counties with persistent poverty.^[9]

• Incidence rises sharply after age 50. Globally, the 70–74-year age group has the most incident cases and deaths.^[8]
• In the United States, the median age at diagnosis is 68 years.^[2] About 70% of patients are diagnosed between ages 55 and 84.^[13]
• Early-onset disease (before age 50) has a distinct epidemiology and is described below.

• Gastric cancer is about 2- to 3-fold more common in men than in women, both worldwide and in the United States.^[3] U.S. incidence is 8.4 per 100,000 per year in men and 4.8 per 100,000 per year in women.^[2]
• Most of the male excess comes from cardia cancer, where the male-to-female incidence rate ratio is about 4.2. For non-cardia cancer the ratio is about 1.6.^[3]
• Incidence in women resembles that in men but lags by roughly 10–15 years after menopause. A protective effect of estrogen has been proposed, but this remains a hypothesis.^[13]
• Early-onset disease runs counter to the overall male predominance: it is relatively more common in women.^[14][4]

• Gastric cancer is one of the few malignancies for which non-Hispanic White Americans have the lowest incidence and mortality.^[12]
• Non-cardia gastric cancer incidence is 1.7- to 3.9-fold higher in Black, Hispanic, Asian/Pacific Islander, American Indian, and Alaska Native individuals than in non-Hispanic White individuals.^[15]
• Korean American men and women aged 50 years or older have the highest risk: up to 12- to 14.5-fold higher non-cardia incidence than non-Hispanic White peers. Korean American men in this age group had a non-cardia incidence of about 70 per 100,000.^[16][9]
• Cardia gastric cancer, by contrast, is more common in White patients.^[14]
• Minoritized groups more often present with regional or distant non-cardia disease.^[17]
• Race and ethnicity are surrogates for underlying drivers: H. pylori prevalence, country of origin, and social determinants of health. Aggregate categories such as “Asian” hide markedly different risk across origin groups, so risk should be assessed by country or region of birth.^[9] Implications for targeted screening are covered in Stomach cancer screening.

Gastric cancer is best understood as two epidemiologically distinct diseases.^[3][1]

• Incidence of gastric cancer diagnosed before age 50 is rising, mainly in low-incidence countries. People born in 1980–1994 have roughly double the rates of those born in the 1950s.^[4]
• In the United States, age-adjusted incidence in people under 50 rose from 2013 to 2022:^[2]
  • Women: 1.2 to 1.8 per 100,000 (average annual percent change [AAPC] 4.0%)
  • Men: 1.5 to 1.6 per 100,000 (AAPC 1.7%)
• Hereditary syndromes account for only about 3% of early-onset cases, mainly hereditary diffuse gastric cancer (CDH1) and Lynch syndrome. Most cases are sporadic.^[4]
• Early-onset disease has distinct biology and presentation. Compared with later-onset disease, it is:^[4][14]
  • enriched for diffuse histology and signet-ring cells
  • more common in women
  • often genomically stable
  • frequently diagnosed at an advanced stage

• Adenocarcinoma accounts for more than 90% of gastric cancers.^[2] It has two Lauren subtypes:
  • Intestinal type: more common in older men; arises through the Correa cascade (chronic gastritis → atrophy → intestinal metaplasia → dysplasia).
  • Diffuse / signet-ring type: affects younger patients, is more often seen in women, and has a worse prognosis.^[2][4]
• Less common subtypes include:
  • gastric neuroendocrine tumors (G-NET)
  • neuroendocrine carcinoma / mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN)
  • gastrointestinal stromal tumors
  • lymphomas, including MALT lymphoma
• SEER 2000–2022 subtype trends:^[19]
  • Adenocarcinoma incidence is falling (AAPC −1.74%).
  • G-NET (AAPC +4.37%) and G-NEC/MiNEN (AAPC +3.67%) incidence is rising, partly because more endoscopy is being performed and more lesions detected.
  • Five-year overall survival is highest for G-NET (~83%) and lowest for gastric carcinoma with a squamous component (~12%).

• GLOBOCAN-based modeling projects about a 62% increase, to roughly 1.77 million new cases a year, by 2040.^[3]
• Lifetime projections for people born in 2008–2017 across 185 countries:^[20]
  • About 15.6 million gastric cancers are expected, about 76% of them attributable to H. pylori and therefore potentially preventable.
  • Two-thirds of these cases are expected in Asia.
  • Sub-Saharan Africa could see roughly six times more cases than current estimates suggest.
• GBD 2023 forecasts that stomach cancer deaths will rise about 22.5%, to about 1.16 million, by 2050, even as age-standardized mortality falls about 36%.^[6]

Detailed risk factors are covered in Stomach cancer risk factors. The factors that most shape the epidemiologic patterns above are:

• H. pylori: an IARC Group 1 carcinogen since 1994. It accounts for 75–90% of non-cardia gastric cancers, and its falling prevalence explains much of the secular decline in incidence.^[3][21]
• Diet and tobacco: The main drivers here are high intake of salt and salt-preserved, smoked, or processed foods, and low fruit and vegetable intake.^[21] In GBD analyses, tobacco is the leading attributable risk factor for gastric cancer mortality after diet.^[8]
• Obesity and GERD: These principally explain cardia/GEJ disease and its different trends in Western populations.^[18]
• Inherited predisposition: About 1–3% of cases (CDH1, Lynch syndrome, BRCA1/BRCA2). In carriers of homologous-recombination gene variants, H. pylori infection markedly amplifies risk.^[4][22]

• Incidence vs prevalence: Older references, including earlier versions of this page, often reported incidence rates as “prevalence.” Incidence, mortality, and survival should be reported as distinct metrics.
• Early-onset drivers are unresolved: Candidate contributors include autoimmune gastritis, gastric microbiome dysbiosis, antibiotic and acid-suppressant use, obesity, and residual hereditary predisposition. Whether the rise is concentrated in cardia disease, non-cardia disease, or both is still debated.^[1]
• Cardia etiology varies by population: The H. pylori-attributable fraction of cardia cancer is about 20% globally, but much higher in some high-incidence populations. A single etiologic model may therefore not apply everywhere.^[1]

Risk for gastric adenocarcinoma (>90% of stomach cancers) is dominated by chronic Helicobacter pylori infection. H. pylori is an IARC Group 1 carcinogen and is associated with roughly 90% of non-cardia (gastric body and antrum) cancers.^[1][2] It drives the stepwise Correa cascade: chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma.^[3][4]

Other modifiable risk factors are tobacco smoking, heavy alcohol use, high dietary salt and salt-preserved foods, processed meat, and obesity. Nonmodifiable factors include older age, male sex, high-risk ancestry or immigration from high-incidence regions, prior partial gastrectomy, prior abdominal radiotherapy, autoimmune gastritis/pernicious anemia, and inherited predisposition. The most important inherited cause is a germline CDH1 pathogenic variant causing hereditary diffuse gastric cancer (HDGC).^[2]

Risk-factor profiles differ by anatomic site and histology:

• Non-cardia, intestinal-type cancer is overwhelmingly H. pylori–driven and arises from precancerous mucosal lesions.
• Cardia/gastroesophageal junction (GEJ) cancer is more closely linked to obesity and gastroesophageal reflux disease (GERD).^[4]
• Diffuse-type cancer can arise without a precursor inflammatory field. This includes the hereditary (CDH1) form.^[5]

• H. pylori has been classified as a Group 1 (definite) carcinogen since 1994. It is the single most important gastric cancer risk factor worldwide.^[1][4]
• Using sensitive immunoblot-based serology, the worldwide attributable fraction for non-cardia gastric cancer is ~89%. Infection is associated with both intestinal- and diffuse-type disease.^[6][7]
• The attributable fraction varies by region and anatomic site:
  • Non-cardia cancer: OR 4.36 in East Asia and 4.03 in the West. H. pylori accounts for an estimated 71.2% of non-cardia cancer in East Asia and 73.2% in the West.^[8]
  • Cardia cancer: a significant association exists only in East Asia (OR 2.86, ~61% attributable), not in Western populations (OR 0.80).^[8]
  • Across 27 countries, more than two-thirds of new gastric cancers in 2022 were attributable to H. pylori. The attributable fraction exceeded 70% in Africa, the Eastern Mediterranean, most of Latin America, China, Japan, and Korea.^[9]
  • Of 15.6 million lifetime gastric cancers projected for people born in 2008–2017, ~76% are attributable to H. pylori.^[10]
• Only a minority of infected people develop cancer: about 3% lifetime, while ~17% develop some precancerous progression. Cancer development depends on co-factors such as oxyntic atrophy, strain virulence, and host and environmental exposures.^[3]
• Strain virulence matters. cagA-positive strains (especially the East Asian EPIYA-D motif) and certain vacA genotypes confer higher non-cardia cancer risk.^[4][3]
• Eradication reduces incidence:
  • In a community cluster-randomized trial (Linqu County, China; 180,284 participants; 11.8 years of follow-up), treatment reduced gastric cancer incidence (HR 0.86; 95% CI 0.74–0.99).
  • The effect was stronger with confirmed eradication (HR 0.81; 95% CI 0.69–0.96).^[11]
  • In patients with gastric intestinal metaplasia, the American Gastroenterological Association (AGA) recommends testing for and eradicating H. pylori (strong recommendation, moderate-quality evidence).^[12]

• EBV-associated gastric carcinoma accounts for ~8–10% of gastric cancers worldwide. It is a distinct TCGA molecular subtype.^[2][13]
• Clinical phenotype: more often proximal (cardia/corpus), more common in men, with prominent lymphocytic infiltration.
• Molecular features: extensive CpG island hypermethylation (e.g., CDKN2A/p16 promoter silencing), frequent PIK3CA mutation, and PD-L1/PD-L2 overexpression.^[5][14]
• A 2025 two-sample Mendelian randomization study found that genetically predicted EBNA-1 antibody levels were associated with gastric cancer (MR-PRESSO OR 1.23; 95% CI 1.05–1.44). This supports a causal contribution.^[15] However, IARC has historically regarded direct causal evidence for gastric cancer as limited.

Atrophic gastritis is defined histologically by loss of gastric glands, usually from chronic H. pylori injury or autoimmunity. The presence of intestinal metaplasia almost always implies atrophy.^[16] Risk rises with lesion severity, histologic subtype, and anatomic extent:

• Corpus-involving or extensive disease carries higher risk than antrum-limited disease.
• Incomplete intestinal metaplasia carries higher risk than complete intestinal metaplasia.
• Risk stratification tools include OLGA/OLGIM histologic staging and the endoscopic Kimura–Takemoto classification (open-type atrophy predicts progression).^[17]

• Autoimmune gastritis causes corpus-predominant autoimmune destruction of oxyntic mucosa. The result is achlorhydria, hypergastrinemia, and enterochromaffin-like cell (ECL-cell) hyperplasia. It is a major cause of atrophic gastritis where H. pylori prevalence is low.^[16]
• Pernicious anemia confers an approximately 7-fold increase in gastric adenocarcinoma risk (most individual studies report 2- to 4-fold). It also predisposes to type 1 gastric neuroendocrine tumors (~0.4–0.7% per year).^[16]

• Tobacco smoking: independent, dose-dependent risk factor (pooled OR ~1.25). About 17–18% of cases are attributable to smoking, and the effect on cardia cancer is stronger.^[2][21][22]
• Heavy alcohol use (≥4 drinks/day): pooled OR ~1.37 vs never-drinkers.^[2][7]
• High salt and salt-preserved or smoked foods (salted fish, pickled vegetables, cured meats): salty-taste preference carries an OR of ~1.59.^[2][23]
  • The effect is amplified in H. pylori–infected individuals.^[24]
• Red and processed meat: consistently associated with increased non-cardia risk.^[24][25]
• Obesity: associated mainly with cardia/GEJ adenocarcinoma through the reflux pathway. The association with non-cardia cancer is inconsistent.^[4][26]
• GERD and Barrett esophagus: risk factors for cardia/GEJ adenocarcinoma.^[3][4]
• Protective factors: diets rich in fresh fruit, vegetables, and fiber. Part of this effect may come from reduced intragastric N-nitroso compound formation.^[27][28]

• Age and sex: >80% of cases are diagnosed at age ≥55 (median 68 years), and incidence in men is roughly twice that in women.^[2] Incidence in people younger than 50 is rising, especially among women.^[2][29]
• Race/ethnicity, immigration, and socioeconomic status: risk is higher in first-generation immigrants from high-incidence regions and in several non-White racial and ethnic groups, including East Asian, Latino, and Eastern European populations. These groups form the basis for targeted screening in low-incidence countries.^[27]
• Prior gastric surgery: risk is increased in the gastric remnant years after distal gastrectomy, attributed to bile and pancreatic juice reflux. Risk is higher after Billroth II than Billroth I reconstruction.^[30]
• Prior radiotherapy: risk is elevated in survivors of Hodgkin lymphoma, testicular cancer, and childhood cancers treated with abdominal radiation.^[31]
• ABO blood group A: incidence ratio ~1.2 vs group O; clinically minor.^[32]

About 10% of gastric cancers show familial aggregation, but defined heritable syndromes account for only ~1–3% of the global burden.^[3][33]

• Definition and genetics:
  • HDGC is an autosomal dominant syndrome of early-onset diffuse (signet-ring cell) gastric cancer and lobular breast cancer.
  • It is caused by germline CDH1 (E-cadherin) pathogenic variants and, less commonly, CTNNA1 (α-catenin) variants.^[34][35]
• Penetrance has been revised downward:
  • Early estimates from families meeting strict clinical criteria placed cumulative gastric cancer risk by age 80 at 70% in men and 56% in women, with a 42% breast cancer risk in women.^[35]
  • In carriers not selected exclusively by clinical criteria, cumulative gastric cancer risk by age 80 was 42% in men and 33% in women, and breast cancer risk was 55%. Earlier estimates were judged inflated by ascertainment bias.^[36]
  • In 213 North American families with CDH1 pathogenic/likely pathogenic variants, cumulative risk of advanced gastric cancer by age 80 was 10.3% in male and 6.5% in female carriers. Breast cancer risk in female carriers was 37%.^[37]
  • Genotype-first data confirm that CDH1 pathogenic and likely pathogenic variants are associated with diffuse gastric and lobular breast cancer. CDH1 missense variants of uncertain significance showed no such association.^[38]
• Natural history: multifocal intramucosal (pT1a) signet-ring cell carcinoma foci are found in >95% of carriers. The incomplete penetrance of advanced disease likely reflects failure of most pT1a foci to progress.^[39]
• Risk reduction: prophylactic total gastrectomy remains the definitive risk-reducing intervention for CDH1/CTNNA1 carriers.^[40][34]
  • Endoscopic surveillance with systematic random biopsies at an expert center is an option for carriers who defer or decline surgery.
  • In a 16-year prospective cohort, omitting random (non-targeted) biopsies would have missed 42% of signet-ring cell carcinoma diagnoses.^[41]